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Journal: Clinical rheumatology


GARDASIL (Merck & Co., Inc., Whitehouse Station, NJ, USA) is a quadrivalent human papillomavirus (HPV4) vaccine. An epidemiological study was undertaken to evaluate concerns about the potential for HPV4 vaccination to induce serious autoimmune adverse events (SAAEs). The vaccine adverse event reporting system (VAERS) database was examined for adverse event reports associated with vaccines administered from January 2006 through December 2012 to recipients between 18 and 39 years old with a listed residence in the USA and a specified female gender. It was observed that cases with the SAAE outcomes of gastroenteritis (odds ratio (OR) = 4.6, 95 % confidence interval (CI) = 1.3-18.5), arthritis (OR = 2.5, 95 % CI = 1.4-4.3), systemic lupus erythematosus (OR = 5.3, 95 % CI = 1.5-20.5), vasculitis (OR = 4, 95 % CI = 1.01-16.4), alopecia (OR = 8.3, 95 % CI = 4.5-15.9), or CNS conditions (OR = 1.8, 95 % CI = 1.04-2.9) were significantly more likely than controls to have received HPV4 vaccine (median onset of SAAE symptoms from 6 to 55 days post-HPV4 vaccination). Cases with the outcomes of Guillain-Barre syndrome (OR = 0.75, 95 % CI = 0.42-1.3) or thrombocytopenia (OR = 1.3, 95 % CI = 0.48-3.5) were no more likely than controls to have received HPV4 vaccine. Cases with the general health outcomes of infection (OR = 0.72, 95 % CI = 0.27-1.7), conjunctivitis (OR = 0.88, 95 % CI = 0.29-2.7), or diarrhea (OR = 1.01, 95 % CI = 0.83-1.22) were no more likely than controls to have received HPV4 vaccine. Previous case series of SAAEs and biological plausibility support the observed results. Additional studies should be conducted to further evaluate the potential biological mechanisms involved in HPV4 vaccine-associated SAAEs in animal model systems, and to examine the potential epidemiological relationship between HPV4 vaccine-associated SAAEs in other databases and populations.

Concepts: Immune system, Epidemiology, HPV vaccine, Rheumatoid arthritis, Rheumatology, Systemic lupus erythematosus, Lupus erythematosus, Antiphospholipid syndrome


This study aims to measure the serum level of 25-hydroxyvitamin D(3) (25-OH-D(3)) in 302 patients with rheumatoid arthritis (RA), studying the association to disease activity. Three hundred two RA patients underwent clinical examination and serological analysis. 25-Hydroxyvitamin D(3) was determined by high-performance liquid chromatography-tandem mass spectrometry. Vitamin D(3) deficiency defined as serum levels of 25-hydroxyvitamin D(3) below 50 nmol/l was detected in 101 RA patients (33.4 %). There was no significant correlation between the serum level of 25-hydroxyvitamin D(3) and Disease Activity Score 28 (DAS28) (3w) score. In a subpopulation of RA patients with very low serum level of 25-OH-D(3) (≤15 nmol/l) (n = 15), there were significant differences compared to patients with normal 25-OH-D(3) (n = 200): higher percentage of patients with positive rheumatoid factor (100.0 versus 77.5 %; p = 0.05), higher CRP (28.7 versus 14.8 mg/l; p = 0.001), higher number of patients treated with at least three disease-modifying antirheumatic drugs (DMARDs) (40.0 versus 14.5 %; p = 0.02), higher number of patients with high disease activity DAS28 score of ≥5.1 (20.0 versus 4.5 %; p = 0.01), lower age (54.5 versus 64.0 years; p = 0.003) and shorter disease duration (5.1 versus 10.3 years; p = 0.06). Deficiency of 25-hydroxyvitamin D(3) was detected in 33.4 % of the RA patients. A subpopulation of patients with severe deficiency of vitamin D(3) serum level of ≤15 nmol/l was characterised by all being positive for rheumatoid factor, high percentage of patients with very high disease activity and high percentage of patients treated with at least three DMARDs.

Concepts: Immunology, Rheumatoid arthritis, Rheumatology, Arthritis, Liquid chromatography-mass spectrometry, Disease-modifying antirheumatic drug, Hydroxychloroquine, Rheumatoid factor


The aim of this study is to investigate the relationship of postural stability and sleep disorders in patients with fibromyalgia syndrome. Frequency of falls in the last 6 months in 48 fibromyalgia and 32 control subjects were recorded. Postural stability was assessed by static posturography device (Tetrax, Sunlight Medical Ltd., Israel). Functional assessment consisted of lower-body strength; one-leg stance test were applied to all subjects. Fibromyalgia impact questionnaire (FIQ), sleep quality numeric rating scale (NRS), and Pittsburgh Sleep Quality Index were inquired. The number of falls in the last 6 months was significantly higher in the fibromyalgia group. Mean total value of stability indexes was 201.7 ± 70.9 vs. 162.6 ± 29.6 in fibromyalgia and control subjects (p < 0.05). NRS and Pittsburgh Sleep Quality Index were significantly higher in fibromyalgia patients. It was detected that there were significant relationships between fall risk and NRS scores (r = 0.565), and FIQ fatigue subscores (r = 0.560) (both p < 0.05). Worse postural performance and fall risk found in the fibromyalgia patients compared to controls were related with the sleep quality in the last 24 h and level of fatigue.

Concepts: Relationship, Sleep, Sleep deprivation, Assessment, Fibromyalgia, Fatigue, Index, Chronic fatigue syndrome


The objective of this study was to investigate the safety and efficacy of a dietary supplement, Arthrem, containing an extract from the medicinal plant Artemisia annua, on pain, stiffness, and functional limitation in osteoarthritis (OA) of the hip or knee. Forty-two patients were randomized to one of three groups (n = 14 in each group): 150-mg Artemisia annua extract (ART) twice daily (BD) (ART low dose), 300-mg ART BD (ART high dose), or placebo BD administered over 12 weeks. Efficacy was assessed using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC®) and visual analog scale (VAS) for pain. Participants treated with ART low dose demonstrated significant improvement in WOMAC total scores from baseline to 12 weeks (mean change, -12.2; standard deviation, [SD] 13.84; p = 0.0159); improvement was not shown in the placebo group (mean change, -7.8; SD, 19.80; p = 0.1029). Statistically significant reductions were seen from baseline in the ART low-dose group for individual WOMAC components stiffness and physical function. VAS pain scores were statistically significantly reduced from baseline to 12 weeks in the ART low-dose group (mean change, -21.4 mm; SD, 23.48 mm; p = 0.0082) but not the placebo group (mean change, -11.5 mm; SD, 28.97 mm, p = 0.1757). No statistically significant changes occurred from baseline in the placebo or ART high-dose groups for any parameter. ART low dose was well tolerated. ART has potential as an anti-inflammatory/analgesic in OA. Treatment with ART 150 mg BD is associated with clinically relevant reductions in pain over 12 weeks. Further studies are warranted.

Concepts: Clinical trial, Statistics, Statistical significance, Dietary supplement, Placebo, Mean, Acupuncture, Standard deviation


Higher levels of moderate to vigorous physical activity improve all-cause mortality and cardiovascular events. However, the effect of running, a moderate to vigorous activity, in those with knee osteoarthritis (OA), a common arthritis that occurs with aging, a high-risk group for mortality and cardiovascular events, is unclear. Therefore, we aimed to evaluate the association of self-selected running on OA symptom and structure progression in people with knee OA. This nested cohort study within the Osteoarthritis Initiative (OAI) (2004-2014) included those at least 50 years old with OA in at least one knee. Runners were defined using a self-administered questionnaire at the 96-month visit. At baseline and 48-months, symptoms were assessed and radiographs were scored for Kellgren-Lawrence (KL) grade (2-4) and medial Joint Space Narrowing (JSN) score (0-3). We evaluated the association of self-selected running with outcomes: KL worsening, medial JSN worsening, new knee pain, and improved knee pain over 48 months, adjusting for baseline age, sex, body mass index (BMI), KL score, contralateral KL score, contralateral knee pain, and injury. If data were not available at the 48-month visit, then they were imputed from the 36-month visit. One thousand two hundred three participants had a mean age of 63.2 (7.9) years, BMI of 29.5 (4.6) kg/m2, 45.3% male, and 11.5% runners. Data from 8% of participants required imputation. Adjusted odds ratios for KL grade worsening and new frequent knee pain were 0.9 (0.6-1.3) and 0.9 (0.6-1.6) respectively. Adjusted odds ratio for frequent knee pain resolution was 1.7 (1.0-2.8). Among individuals 50 years old and older with knee OA, self-selected running is associated with improved knee pain and not with worsening knee pain or radiographically defined structural progression. Therefore, self-selected running, which is likely influenced by knee symptoms and may result in lower intensity and shorter duration sessions of exercise, need not be discouraged in people with knee OA.


Fibromyalgia is a clinical syndrome that currently does not have any specific pathological finding to aid in diagnosis. Therefore, fibromyalgia is most likely a heterogeneous group of diseases with similar symptoms. Identifying and understanding the pathological basis of fibromyalgia will allow physicians to better categorize patients, increasing prospective treatment options, and improving potential therapeutic endeavors. Recent work has demonstrated that approximately 50 % of patients diagnosed with fibromyalgia have damage to their small unmyelinated nerve fibers. A skin punch biopsy is a sensitive and specific diagnostic test for this damage as a reduction in nerve fiber density allows for the diagnosis of small fiber neuropathy. Small fiber neuropathy is a disease with symptoms similar to fibromyalgia, but it often has a definable etiology. Identifying small fiber neuropathy and its underlying cause in fibromyalgia patients provides them with a succinct diagnosis, increases treatment options, and facilitates more specific studies for future therapeutics.

Concepts: Nervous system, Medicine, Medical terms, Biopsy, Diagnosis, Pathology, Axon, Myelin


Low-dose naltrexone (LDN) has been demonstrated to reduce symptom severity in conditions such as fibromyalgia, Crohn’s disease, multiple sclerosis, and complex regional pain syndrome. We review the evidence that LDN may operate as a novel anti-inflammatory agent in the central nervous system, via action on microglial cells. These effects may be unique to low dosages of naltrexone and appear to be entirely independent from naltrexone’s better-known activity on opioid receptors. As a daily oral therapy, LDN is inexpensive and well-tolerated. Despite initial promise of efficacy, the use of LDN for chronic disorders is still highly experimental. Published trials have low sample sizes, and few replications have been performed. We cover the typical usage of LDN in clinical trials, caveats to using the medication, and recommendations for future research and clinical work. LDN may represent one of the first glial cell modulators to be used for the management of chronic pain disorders.

Concepts: Central nervous system, Nervous system, Neuron, Pain, Myelin, Microglia, Chronic pain, Low dose naltrexone


The objective of this study is to examine the proportion of the total treatment effect that is attributable to contextual effects in randomised controlled trials (RCTs) of treatments for fibromyalgia. A systematic literature search was undertaken in Medline, Web of Science, EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Allied and Complementary Medicine in September 2015. The proportion of contextual effect (PCE) was calculated by dividing the improvement in the placebo arm by the improvement in the treatment arm. The measure was log-transformed for each trial and the random effects model was used to pool data. The primary outcome was pain. Secondary outcomes were fibromyalgia impact questionnaire (FIQ) total and fatigue. Heterogeneity was quantified using I 2. Publication bias was assessed using a funnel plot and Egger’s test. Subgroup analysis was undertaken to explore heterogeneity and potential determinants of the PCE. Fifty-one eligible trials (9599 participants) were identified. The PCE was 0.60 (95% CI 0·56 to 0·64) for pain, 0·57 (95% CI 0·53 to 0·61) for FIQ total, and 0·63 (95% CI 0·59 to 0·68) for fatigue. The I 2 was 99.4% for pain, 99.2% for FIQ total, and 97.6% for fatigue. More than half of the treatment effect in fibromyalgia RCTs results from non-specific contextual factors. This suggests that optimising contextual care may enhance treatment effects and improve outcomes. Reporting the total treatment effect and the proportion of contextual effect in trials may help to better translate research evidence into practice.

Concepts: Better, Evidence-based medicine, Systematic review, Randomized controlled trial, Effectiveness, Meta-analysis, Publication bias, Random effects model


This article critically reviews HPV vaccine serious adverse events described in pre-licensure randomized trials and in post-marketing case series. HPV vaccine randomized trials were identified in PubMed. Safety data were extracted. Post-marketing case series describing HPV immunization adverse events were reviewed. Most HPV vaccine randomized trials did not use inert placebo in the control group. Two of the largest randomized trials found significantly more severe adverse events in the tested HPV vaccine arm of the study. Compared to 2871 women receiving aluminum placebo, the group of 2881 women injected with the bivalent HPV vaccine had more deaths on follow-up (14 vs. 3, p = 0.012). Compared to 7078 girls injected with the 4-valent HPV vaccine, 7071 girls receiving the 9-valent dose had more serious systemic adverse events (3.3 vs. 2.6%, p = 0.01). For the 9-valent dose, our calculated number needed to seriously harm is 140 (95% CI, 796-53). The number needed to vaccinate is 1757 (95% CI, 131 to infinity). Practically, none of the serious adverse events occurring in any arm of both studies were judged to be vaccine-related. Pre-clinical trials, post-marketing case series, and the global drug adverse reaction database (VigiBase) describe similar post-HPV immunization symptom clusters. Two of the largest randomized HPV vaccine trials unveiled more severe adverse events in the tested HPV vaccine arm of the study. Nine-valent HPV vaccine has a worrisome number needed to vaccinate/number needed to harm quotient. Pre-clinical trials and post-marketing case series describe similar post-HPV immunization symptoms.

Concepts: Immune system, Human papillomavirus, HPV vaccine, Gardasil, Vaccine, Vaccination


This randomised feasibility study aimed to examine the clinical and biomechanical effects of functional foot orthoses (FFOs) in the treatment of midfoot osteoarthritis (OA) and the feasibility of conducting a full randomised controlled trial. Participants with painful, radiographically confirmed midfoot OA were recruited and randomised to receive either FFOs or a sham control orthosis. Feasibility measures included recruitment and attrition rates, practicality of blinding and adherence rates. Clinical outcome measures were: change from baseline to 12 weeks for severity of pain (numerical rating scale), foot function (Manchester Foot Pain and Disability Index) and patient global impression of change scale. To investigate the biomechanical effect of foot orthoses, in-shoe foot kinematics and plantar pressures were evaluated at 12 weeks. Of the 119 participants screened, 37 were randomised and 33 completed the study (FFO = 18, sham = 15). Compliance with foot orthoses and blinding of the intervention was achieved in three quarters of the group. Both groups reported improvements in pain, function and global impression of change; the FFO group reporting greater improvements compared to the sham group. The biomechanical outcomes indicated the FFO group inverted the hindfoot and increased midfoot maximum plantar force compared to the sham group. The present findings suggest FFOs worn over 12 weeks may provide detectable clinical and biomechanical benefits compared to sham orthoses. This feasibility study provides useful clinical, biomechanical and statistical information for the design and implementation of a definitive randomised controlled trial to evaluate the effectiveness of FFOs in treating painful midfoot OA.

Concepts: Clinical trial, Randomized controlled trial, Effectiveness, Foot, Pharmaceutical industry, Clinical research, Acupuncture, Ankle-foot orthosis